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Targeting of disease‐associated microglia represents a promising therapeutic approach that can be used for the prevention or slowing down neurodegeneration. In this regard, the use of extracellular vesicles (EVs) represents a promising therapeutic approach. However, the molecular mechanisms by which EVs regulate microglial responses remain poorly understood. In the present study, we used EVs derived from human oral mucosa stem cells (OMSCs) to investigate the effects on the lipid raft formation and the phagocytic response of human microglial cells. Lipid raft labeling with fluorescent cholera toxin subunit B conjugates revealed that both EVs and lipopolysaccharide (LPS) by more than two times increased lipid raft formation in human microglia. By contrast, combined treatment with LPS and EVs significantly decreased lipid raft formation indicating possible interference of EVs with the process of LPS‐induced lipid raft formation. Specific inhibition of Toll‐like receptor 4 (TLR4) with anti‐TLR4 antibody as well as inhibition of purinergic P2X4 receptor (P2X4R) with selective antagonist 5‐BDBD inhibited EVs‐ and LPS‐induced lipid raft formation. Selective blockage of αvβ3/αvβ5 integrins with cilengitide suppressed EV‐ and LPS‐induced lipid raft formation in microglia. Furthermore, inhibition of TLR4 and P2X4R prevented EV‐induced phagocytic activity of human microglial cells. We demonstrate that EVs induce lipid raft formation in human microglia through interaction with TLR4, P2X4R, and αVβ3/αVβ5 signaling pathways. Our results provide new insights about the molecular mechanisms regulating EV/microglia interactions and could be used for the development of new therapeutic strategies against neurological disorders. [ABSTRACT FROM AUTHOR]